Lipoxygenases are non-heme iron-containing enzymes that are found in plants and animals and catalyze the oxygenation of particular polyunsaturated fatty acids, such as lipids and lipoproteins. Several different lipoxygenases having particular oxidation reactions are known. Lipoxygenases of a mammal are named according to where they are located in arachidonate that is to be oxygenated. Three types of lipoxygenase of a human are known, and they catalyze addition of oxygen molecules to carbon sites 5, 12 and 15 of arachidonate. Accordingly, the enzymes are named as 5-, 12- or 15-lipoxygenase according to location of a carbon site to which oxygen molecules are added. 5-lipoxygenase converts arachidonate into 5-hydroperoxyeicosatetraenate (5-HPETE). This is a first phase of a metabolism pathway for generating 5-hydroxyeicosatetraenate (5-HETE) and leukotriene (LT). Likewise, 12- and 15-lipoxygenases respectively convert arachidonate into 12-HPETE and 15-HPETE. Biochemical reduction of 12-HPETE induces 15-HETE, which is a precursor of compounds known as 15-HETE lipoxin. Various biological effects are related to products having a lipoxygenase activity, and many of these products are known as mediating factors for various diseases. 15-lipoxygenase is usually expressed in endothelial cells, smooth muscle cells, monocytes/macrophages, glomerulus mesangial cells, renal tubular epithelial cells, and podocytes, and catalyzes formation of 15-S-hydroxyeicosatetraenate (15-S-HETE) from rachidonate (Nataraj an and Nadler, Front. Biosci. (2003) 8:s783-795; Reilly et al., J. Biol. Chem. (2004) 279(10):9440-9450).
Diabetic chronic complications include macrovascular complications, diabetic nephropathy, diabetic neuropathy, etc. If diabetes mellitus continues for several years, microvessels and macrovessels slowly undergo pathologic alteration. Microvascular complications develop directly due to hyperglycemia. If formation of sorbitol is facilitated by hyperglycemia, a thickness of blood vessel walls is increased and blood flow is affected, thereby facilitating blood coagulation. If micro vessel lesions induced by continual hyperglycemia occur in kidney, neurons, etc., diabetic chronic complications, such as diabetic nephropathy diabetic neuropathy, may develop. Meanwhile, hyperglycemia is an indirect cause of macrovascular complications, and an increase in cholesterol due to abnormal lipid metabolism in a hyperglycemia state is a direct cause of hyperglycemia.
Prior art discloses that 15-lipoxygenase is involved in the development of arteriosclerosis, glomerulonephritis, hyperlipidemia, or inflammation. Also, KR 2008-67364 discloses triazole compounds as 15-lipoxygenase inhibitors. However, an agent for preventing or treating such diseases by inhibiting 15-lipoxygenase is not yet commercially available. Thus, there is a need to develop a pharmaceutical composition for preventing or treating such diseases.